{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T08:05:30Z","timestamp":1772179530913,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioinform."],"abstract":"<jats:p>Cathepsin S (CathS) is a cysteine protease known to play a role in extracellular matrix (ECM) re-modelling, antigen presentation, immune cells polarisation, and cancer progression and chronic pain pathophysiology. CathS also causes an immunosuppressive environment in solid tumors and is involved in nociceptive signaling. Although several small-molecule inhibitors with favorable <jats:italic>in vivo<\/jats:italic> properties have been developed, their clinical utility is limited due to resistance, off-target effects, and suboptimal efficacy. Therefore, alternative therapeutic strategies are urgently needed. In the present study, we utilized an integrated virtual screening protocol to screen 3,500 commercially available FDA-approved drug molecules from DrugBank against the CathS crystal structure, based on which drug-likeness profile and interaction studies were performed to filter putative candidates. Alectinib was found to be a top hit and had significant interactions with the important active-site residues His278 and Cys139. PASS predictions suggested relevant anticancer and anti-pain activities for Alectinib in reference to the control inhibitor Q1N. Later, 500-ns molecular dynamics simulations under the CHARMM36 condition revealed that the CathS-Alectinib complex maintained its structural stability, as indicated by conformational parameters, hydrogen-bond persistence, and essential dynamics analyses. Further MM-PBSA calculations also confirmed a favorable binding free energy (\u0394<jats:italic>G<\/jats:italic> \u201320.16 \u00b1 2.59 kcal\/mol) dominated by the van der Waals and electrostatic contributions. These computational findings suggest that Alectinib may have potential as a repurposed CathS inhibitor, warranting further experimental testing in relevant cancer and chronic pain models. Notably, these results are based solely on computational analysis and require empirical validation.<\/jats:p>","DOI":"10.3389\/fbinf.2025.1666573","type":"journal-article","created":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T05:41:10Z","timestamp":1758692470000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational drug repurposing reveals Alectinib as a potential lead targeting Cathepsin S for therapeutic developments against cancer and chronic pain"],"prefix":"10.3389","volume":"5","author":[{"given":"Mohammed","family":"Alrouji","sequence":"first","affiliation":[]},{"given":"Mohammed S.","family":"Alshammari","sequence":"additional","affiliation":[]},{"given":"Sharif","family":"Alhajlah","sequence":"additional","affiliation":[]},{"given":"Syed","family":"Tasqeeruddin","sequence":"additional","affiliation":[]},{"given":"Khuzin","family":"Dinislam","sequence":"additional","affiliation":[]},{"given":"Anas","family":"Shamsi","sequence":"additional","affiliation":[]},{"given":"Saleha","family":"Anwar","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"471","DOI":"10.3390\/pathophysiology31030035","article-title":"Advances in cathepsin s inhibition: challenges and breakthroughs in drug development","volume":"31","author":"Ajani","year":"2024","journal-title":"Pathophysiology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"680021","DOI":"10.3389\/fphar.2021.680021","article-title":"Targeting neuroinflammation in brain cancer: uncovering mechanisms, pharmacological targets, and neuropharmaceutical developments","volume":"12","author":"Alghamri","year":"2021","journal-title":"Front. 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